SUPPOSITORIES AND PESSARIES

Definition:

·         Suppositories are specially shaped solid dosage form of medicament for insertion into body cavities other than mouth.

·         They may be inserted into rectum, vagina or the urethra.

·         This products are so formulated that after insertion, they will either melt or dissolve in the cavity fluids to release the medicament.

Advantages of rectal suppositories:

(i)     Mechanical action: The rectal suppositories are extensively used as a mechanical aid to bowel evacuation which produce its action by either irritating the mucous membrane of the rectum (e.g. glycerol and bisacodyl) or by lubricating action or by mechanical lubrication.

(ii)   Local action: The rectal suppositories may be used for soothing, antiseptic, local anaesthetic action or for astringent effect. Therefore, they may contain

      soothing                 e.g. zinc oxide

      local anaesthetic-  e.g. cinchocaine, benzocaine

      astringents             e.g. bismuth subgallate, hamamelis extract and tannic acid

      antiinflammatory   e.g. hydrocortisone and its acetate.

(iii) To provide systemic action: Suppositories are convenient mode of administration of drugs which irritate the gastrointestinal tract, cause vomiting, are destroyed by the hepatic circulation, or are destroyed in the stomach by pH changes, enzymes etc.

Partial bypass: The lower portion of the rectum affords a large absorption surface area from which the soluble substances can absorb and reach the systemic circulation.

e.g.       aminophylline              used in asthmatic and chronic bronchitis.

            morphine                     a powerful analgesic

            ergotamine tartarate    used to treat migraine

            indomethacin and phenyl butazone     analgesic and anti-inflammatory actions.

Systemic treatment by the rectal route is of particular value for

(a)    treating patients who are unconscious, mentally disturbed or unable to tolerate oral medication because of vomiting or pathological conditions of the alimentary tract.

(b)   administering drugs, such as aminophylline, that cause gastric irritation, and

(c)    treating infants.

PESSARIES

Pessaries are solid medicated preparations for introducing into the vagina, where they melt or dissolve and exert a local action.

They are used mainly for vaginitis (inflammation of the vagina) and leucorrhoea (unpleasant vaginal discharge). Vaginitis may be caused by a variety of micro-organisms or key old age. The medicaments in official pessaries are:

acetarsol          an antiprotozoal agent

di-iodohydroxyquinoline         for yeast and protoplast infections.

lactic acid        often useful in leucorrhoea

nystatin                        for yeast infections

crystal violet    for various microbial infections.

TYPES OF SUPPOSITORIES:

1. Rectal suppositories

These are meant for introduction into the rectum for their systemic effect. They are tapered at one or both ends and usually weigh about 2 gm. The rectal suppositories meant for children are smaller in size and weight is 1 gm.

2. Vaginal suppositories:

They are meant for introduction into vagina.

They are larger than rectal suppositories and vary in weight from 3 to 6 gm or more.

They may be conical, rod-shaped or wedge shaped.

They a re exclusively used for their local action on vagina.

3. Urethral Suppositories (or Urethral bougies)

They are meant for introduction into the urethra.

Their weight varies from 2 to 4 gm and length from 2 to 5 inch. Urethral suppositories are very rarely used.

4. Nasal suppositories (Nasal bougies)

They are meant for introduction into nasal cavity.

They are similar in shape to urethral bougies.

Their weight is about 1 gm and length 9-10 cm.

They are always prepared with glycero-gelatin base.

5. Ear cones (aurinaria)

They are meant for information into the ear.

Generally theobroma oil is used as a base.

They are prepared in an urethral bougies mould and cut according to the required size.

Properties of an Ideal Suppositories Base

1.      It should melt at body temperature or dissolve or disperse in body fluids.

2.      It should release any medicament readily.

3.      It should keep its shape when being handled.

4.      It should be non-toxic and non-irritant to the mucous membrane.

5.      It should be stable on storage.

6.      It should be compatible with any added medicament.

7.      It should be stable if heated above its melting point.

8.      It should be easily moulded and should not adhere to the mould.

9.      It should be easily mouldable by pouring or cold compression.

[Since it is not possible to get all the above mentioned qualities in a single base, so a combination of bases is used to get a product of required qualities. A number of patent “improved” suppository bases are available. Most of these are mixtures of fats, waxes and/or esters in specific proportions according to the desired qualities of the product to be obtained. Glycerogelatin and polyethylene glycols are being widely used as suppository bases, though theobroma oil is extensively used in extemporaneous preparations but it is losing its importance because it is unstable to heat and has undesirable physical properties.]

Types of Suppository Bases

Suppository bases fall into two classes -

1. Fatty bases - these melt at body temperature.

2. Water-soluble or water miscible bases - these dissolve or disperse in rectal secretions.

3. Emulsifying bases

FATTY BASES

Theobroma oil (Cocoa butter)

It is a yellowish-white solid with a chocolate-like odour. It is a mixture of glyceryl esters of stearic, palmitic, oleic and other fatty acids. Its valuable characteristics include -

Advantages:

(a)    A melting point range of 30 to 36 ⁰C; hence it is solid at normal room temperatures but melts in the body.

(b)   Ready liquefaction on warming and rapid setting on cooling.

(c)    Miscibility with many ingredients.

(d)   Blandness i.e. does not produce irritation.

Disadvantages:

(a) Polymorphism

When melted and cooled it solidifies in different crystalline forms, depending on the temperature of melting, rate of cooling and size of the mass. If melted at not more than 36⁰C and slowly cooled it forms stable beta crystals with normal melting point, but if over-heated it may produce, on cooling, unstable gamma crystals, which melt at about 15⁰C, or a-crystals, melting at about 20⁰C. These unstable forms eventually return to the stable condition but this may take several days and meanwhile, the suppositories may not set at room temperature or, if set by cooling, may remelt in the warmth of the patient’s home.

This lowering of the solidification point can also lead to sedimentation of suspended solids and delay in issuing the product to the patient. Consequently, great care must be taken to avoid over-heating the base when making theobroma oil suppositories.

(b) Adherence to mould

Because theobroma oil doesn’t contract enough on cooling to loosen the suppositories in the mould, sticking may occur, particularly if the mould is worn. This is prevented by lubricating the mould before use.

(c) Softening point too low for hot climates

To raise the softening point, whit beeswax may be added to theobroma oil suppositories intended for use in tropical and subtropical countries.

(d) Melting point reduced by soluble ingredients

Substances, such as chloral hydrate, that dissolve in theobroma oil, may lower its melting point to such an extent that the suppositories are too soft for use. To restore the melting point, a controlled amount of white beeswax may be added.

(e) Slow deterioration during storage

This is due to oxidation of the unsaturated glycerides.

(f) Poor water absorbing capacity

This fault can be improved by the addition of emulsifying agents.

(g) Leakage from the body

Sometimes melted base escapes from the rectum or vagina. This is most troublesome with pessaries because of their larger size, and therefore, these are rarely made with theobroma oil.

(h) Relatively high cost

Synthetic fats

As a substitute of theobroma oil  a number of hydrogenated oils, e.g. hydrogenated edible oil, arachis oil, coconut oil, palm kernel oil, stearic and a mixture of oleic and stearic acids are recommended.

N.B. Synthetic suppositories bases are by hydrogenation and subsequent heat treatment of vegetable oils such as palm oil and arachis oil. The oils are generally esters of unsaturated fatty acids. Hydrogenation saturates the unsaturated fatty acids and heat treatment splits some of the triglycerides into fatty acids and partial esters (mono- and di-glycerides).

Advantages of these synthetic fats over theobroma oil:

1.      Their solidifying points are unaffected by overheating.

2.      They have good resistance to oxidation because their unsaturated fatty acids have been reduced.

3.      Their emulsifying and water absorbing capacities are good. [They usually contain a proportion of partial glycerides some of which, e.g. glyceryl monostearate, are w/o emulsifying agents and, therefore, their emulsifying and water absorbing capacity are good.

4.      No mould lubricant is required because they contract significantly on cooling.

5.      They produce colorless, odourless and elegant suppositories.

Disadvantages:

1.      They should not be cooled in refrigerator because they become brittle if cooled quickly. Certain additives e.g. 0.05 % polysorbate80, help to correct this fault.

2.      They are more fluid than theobroma oil when melted and at this stage sedimentation rate is greater. Thickeners such as magnesium stearate , bentonite and colloidal silicon dioxide, may be added to reduce this.

WATER SOLUBLE AND WATER MISCIBLE BASES

Glycero-Gelatin base

·         This is a mixture of glycerol and water made into a stiff jelly by adding gelatin.

·         It is used for the preparation of jellies, suppositories and pessaries. The stiffness of the mass depends upon the proportion of gelatin used which is adjusted according to its use.

·         The base being hydrophilic in nature, slowly dissolves in the aqueous secretions and provide a slow continuous release of medicament. Glycerogelatin base is well suited for suppositories containing belladonna extract, boric acid, chloral hydrate, bromides, iodides, iodoform, opium, etc.

·         Depending upon the compatibility of the drugs used a suitable type of gelatin is selected for the purpose. Two types of gelatins are used as suppository base

(i)         Type-A or Pharmagel-A which is made by acid hydrolysis (has isoelectric point between 7 to 9 and on the acid side of the range behaves as a cationic agent, being most effective at pH 7 to 8. ) is      used for acidic drugs.

(ii)        Type-B or Pharmagel-B which is prepared by alkaline hydrolysis (having an isoelectric point              between 4.7 to 5 and on the alkaline side of the range behaves as an anionic agent, being most effective at pH 7         to 8 ) is used for alkaline drugs

Disadvantages:

Glycerogelain base suppositories are less commonly used than the fatty base suppositories because:

(i)     Glycerol has laxative action.

(ii)   They are more difficult to prepare and handle.

(iii) Their solution time depends on the content and quality of the gelatin and the age of the base.

(iv) They are hygroscope, hence must be carefully stored.

(v)   Gelatin is incompatible with drugs those precipitate with the protein e.g. tannic acid, ferric chloride, gallic acid, etc.

Soap-Glycerin Suppositories

·         In this case gelatin and curd soap or sodium stearate which makes the glycerin sufficiently hard for suppositories and a large quantity of glycerin upto 95% of the mass can be incorporated.

·         Further the soap helps in the evacuation of glycerin.

·         The soap glycerin suppositories have the disadvantage that they are very hygroscopic, therefore they must be protected from atmosphere and wrapped in waxed paper or tin foil.

Polyethylene glycol bases / Macrogol bases (Carbowaxes)

Depending on their molecular weight they are available in different physical forms.

Examples of Macrogol bases:

	I	II	III	IV
Macrogol 400 Macrogol 1000 Macrogol 1540 Macrogol 4000 Macrogol 6000 Water	- - - 33 47 20	- - 33 - 47 20	20 - 33 - 47 -	- 75 - 25 - -

By choosing a suitable combination a suppository base with the desired characteristics can be prepared.

Advantages:

1.      The mixtures generally have a melting point above 42⁰C, hence, does not require cool storage and they are satisfactory for use in hot climate.

2.      Because of the high melting point they do not melt in the body cavity, rather they gradually dissolve and disperse, releasing the drug slowly.

3.      They do not stick to the wall of the mould since they contract significantly on cooling.

EMULSIFYING BASES

These are synthetic bases and a number of proprietary bases of very good quality are available, few of which are described below:

Witepsol

They consist of triglycerides of saturated vegetable acids (chain length C12 to C18) with varying proportions of partial esters.

Massa Esterium

This is another range of bases, consisting of a mixture of di-, tri- and mono- glycerides of saturated fatty acids with chain lengths of C11 to C17.

Massuppol

It consists of glyceryl esters mainly of lauric acid, to which a small amount of glyceryl monostearate has been added to improve its water absorbing  capacity.

Advantages of these bases over cocoa butter:

1.      Over heating does not alter the physical characteristics.

2.      They do not stick to the mould. They do not require previous lubrication of the mould

3.      They solidify rapidly.

4.      They are less liable to get rancid.

5.      They can  absorb fairly large amount of aqueous liquids.

PREPARATION OF SUPPOSITORIES

Suppositories are prepared by two processes: moulding (hot process or fusion process) and cold compression.

Mould

Various types and sizes of suppository moulds are available. In the dispensary suppository moulds with six or twelve cavities with desired shape and size may be used. For large scale production moulds up to 500 cavities may be used.

Moulds are made up of stainless steel, nickel-copper alloy, brass, aluminium or plastic.

For cleaning, lubrication and removal of suppositories the mould can be opened longitudinally by removing the screw in the centre of the plates.

The nominal capacities of the common moulds are 1g, 2g, 4g and 8g.

Calibration of the mould

The nominal capacity of a mould is not always correct. It will vary for different bases. Each mould should be calibrated before use by preparing a set of suppositories or pessaries using the base alone, weighing the products and taking the mean weight as the true capacity. This is repeated for each base and the value is recorded for future use.

Displacement value

The volume of a suppository from a particular mould is uniform but its weight will vary because the densities of medicaments  usually differ from the density of the base with which the mould was calibrated.

To prepare products accurately, allowance must be made for the change in density of the mass due to added medicaments. For this purpose the displacement value of a medicament is taken into consideration.

Definition: The number of parts of medicament (drug) that displaces one part by weight of the base is known as the displacement value of that drug.

The following table lists the displacement values, with reference to theobroma oil, for substances prescribed in suppositories and pessaries.

Table

Aminophylline Bismuth subgallate Castor oil Chloral hydrate Cinchocaine Hydrochloride Cocaine hydrochloride Hydrocortisone

1.5 3.0 1.0 1.5 1.5 1.5 1.5

Hydrocortisone acetate Ichthammol Morphine Hydrochloride Phenobarbitone Resorcinol Tannic acid Zinc oxide

1.5 1.0 1.5 1.0 1.0 1.0 5.0

Example:-

To prepare ten suppositories each containing 300 mg bismuth subgallate.

Mould size is 1 g.

Displacement value of bismuth subgallate is 3.

300 mg bismuth subgallate = 0.3 g bismuth subgallate

Displacement value of bismuth subgallate means 3 g bismuth subgallate displaces 1 g theobroma oil.

Therefore, 0.3 g bismuthsubgallate will displace

(1 ¸ 3) ´ 0.3 = 0.1 g     suppository base (i.e. theobroma oil)

So the working formula for each suppository will be

                                                Bismuth subgallate                   0.3g

                                                Theobroma oil                         0.9g

                                                Total                                        1.2g

Determination of Displacement value of a Medicament

The displacement value of a given medicament can be determined as follows:

·         Six suppositories are prepared with theobroma oil only (or other base) and their total weight =a mg

·         Six suppositories are prepared containing 40% of the medicament and their total weight = b mg.

·         Amount of theobroma oil = c mg              = 60% of b  mg                        = 0.6 ´ b mg

·         Amount of medicament     = d mg                         = 40% of b mg                         = 0.4 ´ b mg

·         The weight of theobroma oil displaced by d  mg of medicament = (a - c) mg

·         Displacement value of the medicament = d / (a - c)  mg

For example:

Weight of six unmedicated suppositories       = 6g

Weight of six suppositories containing 40% of zinc oxide          = 8.8 g

                                                                     60
Theobroma oil in this                          =  ---    ´  8.8   =  5.28 mg
                                                                    100

                                                                     40
Zinc oxide in this                                 =  ---    ´  8.8   =  3.52 mg
                                                                    100

Theobroma oil displaced by 3.52 g of zinc oxide                         = 6 - 5.28  =  0.72 g

Therefore, the displacement value of zinc oxide                 =   3.52 / 0.72   =  5 (approximately)

Lubrication of Moulds

·         If the cavities of the mould are imperfect, i.e. poorly polished or scratched, it may be difficult to remove the cocoa butter suppositories without damaging their surfaces unless a lubricant is used. In this case an aqueous lubricant is used.

·         Glecero-gelatin base is sticky in nature hence they are lubricated with an oily lubricant e.g. liquid paraffin or arachis oil.

·         It is unnecessary to lubricate the mould when synthetic fat or macrogol bases are used. The products have better surface if the mould is dry.

For theobroma oil the following lubricating preparation is found to be useful:

                        Soft Soap                     10 g

                        Glycerol                       10 ml

                        Alcohol (90 %)                        50 ml

The lubricant should be applied on a pad of gauze or muslin, or with a small fairly stiff brush.

To avoid excess lubrication the moulds are closed and kept inverted on a clean tile to drain out excess lubricant.